6FNM

Crystal Structure of Ephrin B4 (EphB4) Receptor Protein Kinase with Dasatinib

Summary for 6FNM

• Entry DOI: 10.2210/pdb6fnm/pdb
• Descriptor: Ephrin type-B receptor 4, N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE (3 entities in total)
• Functional Keywords: inhibitor, complex, protein tyrosine kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33976.36

Authors

Kudlinzki, D.,Troester, A.,Witt, K.,Linhard, V.L.,Saxena, K.,Schwalbe, H. (deposition date: 2018-02-04, release date: 2018-08-08, Last modification date: 2024-01-17)

Primary citation

Troster, A.,Heinzlmeir, S.,Berger, B.T.,Gande, S.L.,Saxena, K.,Sreeramulu, S.,Linhard, V.,Nasiri, A.H.,Bolte, M.,Muller, S.,Kuster, B.,Medard, G.,Kudlinzki, D.,Schwalbe, H.
NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family.
ChemMedChem, 13:1629-1633, 2018

PubMed Abstract: Erythropoietin-producing hepatocellular (EPH) receptors are transmembrane receptor tyrosine kinases. Their extracellular domains bind specifically to ephrin A/B ligands, and this binding modulates intracellular kinase activity. EPHs are key players in bidirectional intercellular signaling, controlling cell morphology, adhesion, and migration. They are increasingly recognized as cancer drug targets. We analyzed the binding of NVP-BHG712 (NVP) to EPHA2 and EPHB4. Unexpectedly, all tested commercially available NVP samples turned out to be a regioisomer (NVPiso) of the inhibitor, initially described in a Novartis patent application. They only differ by the localization of a single methyl group on either one of two adjacent nitrogen atoms. The two compounds of identical mass revealed different binding modes. Furthermore, both in vitro and in vivo experiments showed that the isomers differ in their kinase affinity and selectivity.

PubMed: 29928781
DOI: 10.1002/cmdc.201800398

Experimental method

X-RAY DIFFRACTION (1.157 Å)